6-fluoro-9alpha, 11beta- 21-trihalo-progesterones



3,009,932 -TRlHALO-PROGESTERONES Hans Reimanu, Bloomfield, and David H. Gould, Leonia,

N.J., assignors to Schering Corporation, Bloomfield,

N.J., a corporation of New Jersey No Drawing. Filed June 1, 1959, Ser. No. 817,055 r 20 Claims. '(Cl. 260-3973) This invention relates to novel and therapeutically useful halogenated steroids and to methods for their. manufacture.

In particular, this invention relates to 6,l7,2l-trisubstituted-9a,llB-dihalogenated derivatives of progesterone which exhibit valuable progestational prop erties.

Our novel compounds may be represented by the following formula:

'wherein X is a halogen having an atomic weight greater than 19; Y is a halogen having an atomic weight less than 126 and being at least as electro-negative as X; R is a member of the group consisting of bromine, hydroxy, and acyloxy; W is a member of the group consisting of fluorine; Z is halogen preferably fluorine or iodine; and

the l-dehydro analogs thereof. The bond designated by the wavy line in the above formula indicates that the substituent at the 6-carbon may be in an aor 3- position. In this application whenever the configuration at 6 is not specifically designated as a or 13, both configurations are included. These novel compounds are thus 6,9,11,17,21-pentahalogenated analogs, l7-hydroxy-, and 17-acyloxy-6,9,l1,21-tetrahalogenated analogs, of progesterone and l-dehydroprogesterone.

Illustrative of the l7a-acyl groups in the l7e-acyloxy derivatives contemplated by our invention are lower alkanoates such as formate, acetate, propionate, butyrate, isobutyrate, valerate, isovalerate, pivalate, caproate, enanthate; substituted alkanoates such as fi-cyclopentyL propionate, cyclohexylacetate, ethoxyacetate, phenylacetate, phenoxyacetate; unsaturated acyl radicals such as acrylate and crotonate, aromatic acyl radicals such as benzoate and toluate, as well as the residues of dibasic .9a,1lfl-dichloro-l7a-hydroxyprogesterone l7-acetate), 6-

fluoro 9e,llB dichloro 2l-iodo-l7a-acetoxyprogester ones, 60:,1 119,21 trifiuoro 9a-bromo-l7a-acetoxyprogesprogesterone, 611,2 l-difillOl'O-9a,l lfi-dichloro-lh-bromoprogesterone, as well as their l-dehydro analogs. Although our compounds (with the exception of the 17- hydroxy substituted compounds which are valuable as intermediates) are, in general, valuable progestins, the

6a-substituted-l7a-acyloxy-2l-fiuoroprogesterones of the general formula are the preferred species and in particu- Ice 1 lar, 6a,21-difiuoro-9a,llp-dichloro-l7erhydroxyprogest one l7-acetate.

In the above'formula, the halogen at 0-11 must at least as electronegative as the halogen present in 9a-position (fluorine being the most electronegative ha gen, and iodine the least electronegative) and furtl cannot be iodo. Thus, a progesteroneof our invent containing a 9a-chloro group may possess an llfl-Chit or an lie-fluoro group, but cannot contain an llB-ic or llp-bromo group. This artificial restriction as to electronegativity of .the 9 and ll-s'ubstituents is net sarily imposed in view of the limitations or the men facturing process developed below.

Our novel compounds are prepared .by reacting a 4 (1l)-pregnad iene-3,20-dione substituted at the 6-eart by fluorine, at the 17-carbon by hydroxy, 'acyloxy, ha gen, and at the 2l-carbon preferably by fluorine iodine (or a similarly substituted l,4,9(ll)-pregnatrie 3,20-dione) with a suitable halogenating agent. '1

starting compounds utilized in this invention are thereft exemplified by compounds such as 6,2l-difiuoro-l acetoxy 4,9( ll) pregnadiene-3,20-diones, tS-fluoro-i iodo 17 acetoxy-4,9( ll)-pregnadiene-3,20-diones, well as the unesterified l7u-hydroxy analogs of the to going, 6,2l-difluoro-l7a-bromo-4,9( 1 l )-pregnadiene-,3,f diones, and the l-dehydro analogs of the foregoing.

The starting materials thus necessarily possess A -bond, and are prepared .by a combination of pr esses analogous to those described in the literature. 1 example, a l7a-hydroxy-2l-fluoro-4,9(1l)pregnadie 3,20-dione is conveniently converted to the l7a-acylc analog upon esterification oi thelhhydroxypregnadie according to known techniques such as with acetic a in the presence of trifluoroacetic anhydride or a suita. acid anhydride (such as acetic) in the presence of acidic catalyst such as p-toluenesulfonic acid. By'sl stituting other lower alkanoic acids such as p-cyclopent propionic and caproic for acetic acid in the above este fication procedures, other l7u-lowersalkanoate starti compounds are obtained such as the l'ia-(fl-cyclopent propionate) and l7-caproate respectively.

60: fluoro 21-iodo-17-acetoxy-4,9(1l)-pregnadie1 droprogesterone) is prepared from 6a-fiuoro-l7a,2lhydroxy-4,9( l 1 )-pregnadiene-3,20-dione by conversion the ZI-sulfonate ester followed by reaction with S0dil iodide and subsequent esterification of the l7-hydro: group in the 6a-fiuoro-21-iodo-l7u-hydroxy-4,9'(l pregnadiene 3,20-dione (6a-fiuoro-2l-iodo-Hat-hydro progesterone) thereby produced. I

To obtain 6,l7e,21-trisubstituted-9(11)-dehydropr0g terones from a flat-substituted progesterone such as l bromoprogesterone, known chemical techniques are e ployed.

An llu-hydroxyl group, instead of an lip-hydro: group, may be introduced into a 6,17-disubstituteddesoxyprogesterone through the action of a microorgani such as Rhizopus nigricans (A.T.C.C. 6227b) using p cedures analogous to those described in US. Patent 1 2,602,769. Subsequent treatment of the Ila-hydro: progesterone derivative so obtained with a sulfonyl ch ride such as methanesulfonyl chloride or toluenesulfo: chloride yields the corresponding llu-sulfonate wh when treated with a base such as pyridine gives the sired 6,l7-disubstituted-9( l 1)-dehydroprogesterone dei ative.

In like manner, G-substituted-17a-bromo-4,9(1l)-pr nadiene starting compounds, such as 6a-tluoro-l7e-bron 4,9 (11) pregnadiene 3,20-dione (6a-fluoro-l7a-bron 9(1l)-dehydroprogesterone) are obtained from. i bromoprogesterone through the sequence of 'reactit described in the above paragraphs.

dine is introduced into the 2l-position of the 6 tituted-l7a-bromo-4,9(1l) pregnadienes described we by known procedures such as, for example, that :h utilizes iodine and finely powdered calcium oxide, producing requisite 9(1l)-dehydro starting comnds such as for example, 6a-fiUOl'O-l7a-bt0mO-2l- |-4,9( l l )-pregnadiene-3,20-dione (fia-fillOIO-l'lu-DI'O- 2l-iodo-9( 1 l -dehydroprogesterone) he 2l-fluoro-A -intermediates are obtained from r corresponding 2l-iodo analogs by the action of, example, silver fluoride in moist acetonitrile to give lisite intermediates such as 60:,21-difiUOI'O-l7ot-1JY- ry-4,9(ll)-pregnadiene-3,20-dione (6a,21 r difluoro- -hydroxy-9( l l )-dehydroprogesterone) and 6a,2l-diro-l7a-bromo-4,9( l l )-pregnadiene-3,20-dione (6a,2lloro-l7e-bromo-9(l l)-dehydroprogesterone). A 6-subted 2l-fluoro-l7m-hydroxy intermediate thus pro- :d is easily esterified by previously described prolres to give a corresponding 17a-acyloxy intermediate l as 611,2l-difluoro-l7a-acetoxy-4,9( 1 1 -pregnadienedione (6a,21-difiuoro-l7u-acetoxy-9( 1 l )-dehydrogesterone). I he l-dehydro intermediates, i.e. the 6,2l-ditluoro-, 6- ro-, 2 l-iodo-, 17-bromo-l,9( l 1 -bisdehydroprogesbe, 170: hydroxy-l,9(1l)-bisdehydroprogesterone, l7a-acyloxy-l,9( l l )-bisdehydroprogesterone are pre- :d from the corresponding 1,2-dihydro intermediates microbiological dehydrogenation with an organism l as, for example, Corynebacterium simplex (A.T.C.C. 6) in a manner similar to that described in US. am No. 2,837,464, or by chemical dehydrogenation tugh the use of such reagents as chloranil orseleninm tide. [alogenating agents suitable for use in our process 1) Molecular halogens having a molecular weight iter than 38 and less than 253. This class includes :roatomic halogen molecules such as iodine mono- )ride as well as isoatomic halogen molecules such as nine and bromine. The molecular halogen emved may be used alone or in admixture with a halide in. In reactions employing isoatomic molecular agens an anion corresponding to the molecular halois used. For example, in reactions using molecular Jrine, a suitable chloride salt such as lithium chloride hydrochloric acid are suitable anion sources. In reons which employ a heteroatomic molecular halogen, ource of the more electronegative anion is used, i.e. uitable chloride salt or hydrochloric acid is used in a :tion employing iodine monochloride. 2) Addition compounds of molecular halogens, said lecular halogens having a molecular weight greater n 38 and less than 253. Examples of such addition apounds are pyridinium bromide perbromide, pyridinichloride perchloride, dioxane dibromide, iodobene dichloride, and the like. 3) N-haloamides in admixture with a halide anion, halogen in the middle being at least as electronegative the halogen cation in the N-haloamide, and the comed molecular weight of said halogens being greater n 38 and less than 253. N-haloarnides used in these rtures are such as N-chlorosuccinimide, N-bromoacetide, dimethyl-N,N-dibromohydantoin, N-iodosuccindo and the like. Examples of mixtures of N-haloide and a halide are such as N-chlorosuccinimide and lrogen chloride; N-bromoacetamide and hydrogen brote; N-bromoacetamideand lithium chloride; N-broacetamide and hydrogen fluoride; N-iodosuccinde and sodium chloride. These mixtures may have re than one source of halide ion such as in the re- :nt combination N-chlorosuccinimide, hydrogen chloe and lithium chloride. Molecular halogens (both isoatomic and heteroatomic) such as chlorine, bromine and iodine mornochloride, and molecular halogen addition compounds such as iodobenzene dichloride or pyridinium bromide perbromide employed in our process may be used directly in their commercially available form, in which case they are added directly. to the reaction mixture either alone or in a suitable-non-reacting solvent such as acetic acid or tetrahydrofuran. The halogenating agent is preferably used in approximately equivalent quantities to that of the steroid.

Alternatively, the halogenating reactant may be prepared in situ. For example, 0.9-1.2 equivalents of halogen cation (based on the amount of steroid) such as is obtained from N-bromosuccinimide is added to a reaction mixture containing a halogen anion of greater or equal electronegativity than the cationic reagent. The halogen anion may be supplied by a hydrohalic acid or by a salt such as sodium bromide, lithium chloride, potassium fluoride, or by mixtures of a hydrohalic acid with an alkali metal halide. Whenever an acid is the source of a halogen anion, approximate theoretical quantities are generally used; whereas if a salt is used as the halogen anion source it may be present in large excess. Such an excess of anion is frequently useful to obtain an increased yield or greater purity of product.

Thus, each of our novel compounds may be prepared by any one of several methods. For example, 6a,2l-difiuoro-l7u-hydroxy-9ed 1,8 dichloroprogesterone l7-acetate may be prepared from 6e,2l-difiuoro-lh-hydroxy- 9(11)-dehydroprogesterone l7-acetate by utilizing such reagents and combinations as (1) chlorine and lithium chloride, (2) N-chlorosuccinimide and lithium chloride, (3) sodium chloride, N-chlorosuccinimide together with hydrogen chloride, (4) chlorine alone, (5) chlorine and hydrogen chloride, and (6) iodobenzene dichloride.

An alternate route for preparing 6,21-disubstituted-. l7a-acyloxy compounds falling under the general formula isv by halogenating a 6,2l-disubstituted-l7a-hydroxy-9(l1)-dehydroprogesterone (or the l-dehydro analog) by any of the above described halogenating methods of our invention, with subsequent esterification of the 6,2l-disubstituted-9a,1lfi-dihalogenodh-hydroxyprogesterone (or the l-dehydro analog) thereby obtained.

In this manner, 6,2l-difluoro-17e-hydroxy-9(ll)-dehydroprogesterone, upon chlorination with a reagent such as chlorine in carbon tetrachloride in the presence of pyridine yields 6a,2l-dlflu0l0-9a,llfl dichloro-lh-hydroxyprogesterone which when esterified with acetic acid and trifluoroacetic anhydride, for example, gives-6e31- difiuoro-9a,l l fl-dichloro-17e-hydroxyprogesterone l7-acetate. Other acids may be substituted for acetic acid in the esterification step to obtain the corresponding 17::- acyloxy dihalogenated progesterone.

Our novel halogenating process is also useful in preparing the l-dehydro compounds falling under the general formula. Thus, a 6,17,2l-trisubstituted-9u,llfi-dihalogeno-l-dehydroprogesterone falling under the general formula by utilizing any one of the six reagents and combinations listed previously. In addition, our novel halogenated l-dehydroprogesterones are obtained from the corresponding halogenated progesterones by microbiological or chemical dehydrogenation techniques as heretofore described.

Our process, whereby a 6,l7a,2l-trisubstituted-9(ll)- v dehydroprogesterone is converted to a 6,l7a,21-trisubstitutcd-9a,llB-dihalogeno derivative, is generally carried out in the presence of a non-reacting solvent at temperatures ranging from 5 C. to 50 C. with reaction times varying from one-half hour to 24 hours, depending on the reagents involved. It is preferred that the halogen cation source be present in amounts of 0.9-1.2 equivalents based upon the amount of steroid. The choice of solvent in each reaction is naturally determined by the solubility of the reactants in the process. A preferred reaction condition employs glacial acetic acid as the sole or major solvent with the reaction being carried out at room temperature for a period of approximately two hours.

Although glacial acetic acid is frequently the preferred solvent, other solvents are used in dihalogenation process either alone or in combination with acetic acid. Other solvents which may be employed include lower aliphatic acids such as propionic and diethylacetic, halogenated hydrocarbons such as methylene chloride and chloroform, saturated ethers such as tetrahydrofuran and dioxane, and inert solvents such as dimethyl sulfoxide, as well as suitable mixtures of these solvents.

Further we have found that when carrying out the halogenation process in a halogenated hydrocarbon solvent such as methylene chloride, chloroform or carbon tetrachloride, the yield and purity of the dihalogenated progesterone obtained is greatly increased by adding pyridine to the reaction mixture. Preferably up to ten equivalents of pyridine are added and usually one to four, based on the amount of steroid being converted. Other organic basic agents which may also be used in conjunction with a halogenated hydrocarbon solvent are aromatic tertiary amines such as lutidine, collidine, alkyl substituted pyridines and the like. The reaction is usually carried out initially at 20 C. with subsequent warming to about room temperature. The reaction time may be as short as five minutes or as long as several hours. In general, the optimum reaction time is about one hour.

Our novel 6,l7a,2l-trisubstituted dihalogenated progesterones and the l-dehydro analogs (except those having a free hydroxyl group at C-l7) are active progestational agents by both oral and intramuscular routes, being specific in their action and devoid of androgenic, es'trogenic or corticoid activity. That our compounds have progestational activity at all is surprising in view of the art which teaches that the introduction of substituents into the C-ring of progesterone and its derivatives, such as for example, llfl-hydroxyprogesterone and the acetate thereof, eliminates progestational activity or reduces it to such an extent that the compounds are useless for therapeutic purposes. Our C-ring halogen substituted progesterones, on the other hand, are significantly more active than progesterone by the intramuscular route. Orally our compounds are comparable in activity to ethisterone, the known standard progestational agent.

In addition to being active both orally and intramuscularly, our halogenated progestins possess the added advantage of having a minimum effect on water, sodium and potassium metabolism. Thus, they may be administeredwithout causing the usual side effects associated with electrolyte imbalance.

Our therapeutically active compounds are useful for the treatment of conditions requiring progestational agents such as the maintenance of pregnancy, or treatment of functional dysmenorrhea, premenstrual tension, habitual or threatened abortion. When administered orally, our compounds are preferably used in the form of tablets containing from to 100 mg. together with the excipients such as starch or milk sugar. For subcutaneous and intramuscular administration, solutions or suspensions of our compounds with a non-toxic liquid vehicle are used. The dosage required may vary with the indications being treated and may range from about 10 to 25 mg. daily.

Our halogenated progestins are also valuable in the veterinary field for treating conditions in both large and small animals which require a progestational agent. In breeding animals, for example, our compounds are useful in preventing threatened abortion. Additional uses are in controlling egg and milk production by regulating the cycle of chickens and cows by the administration of our progestational agents.

The 6 substituted-l7a-hydroxy-9J1,21-trihalogcnated progesterones and their l-dehydro analogs are valuab as intermediates in the preparation of the G-substitute l7a-acyloxy-9,l1,21-trihalogenated progesterones, Whit are active progestins. In addition, the 6-substituted-17 hydroxy-21-fluoro-9.1l-dihalogenated progesterones pr duced by our process, and particularly the l-dehydl analogs, possess anti-inflammatory activity, thus renderir these compounds therapeutically valuable per se.

The following examples are illustrative of the proc dures employed in preparing the compounds of this i1 vention, but are not to be construed as limiting the sec thereof; the scope of our invention being limited only l the appended claims.

- EXAMPLE 1 6 a-methyl-I Ia-hydroxy-ZI -iodo-4,9(I 1 )-pregnadiene- 3.20-dione A. Ga-METHYLUm,21-DIHYDROXY-4,9 11 -PREGNA- DIENE-3,20-DIONE ill-ACETATE A mixture of 2.0 g. of the pregnadiene of Example 1. and ml. of 0.27 N methanolic perchloric acid is stirre at room temperature for 18 hours. The reaction mi: ture is poured into water and the precipitate which forn is filtered and recrystallized from acetone to give 6i methyl-17a,2l-dihydroxy-4,9( 1 1 -pregnadiene-3,20-dion C. Ga-METHYL-l 7e,21-DIHYDROXY-4,9 11 -PB.EGNA- DIENE-3,20-DIONE 21-METHANESULFONATE A solution of 10 g. of 6a-methyl-17a,2l-dihydroxy 4,! (1l)-pregnadiene-3,20-dione (the compound of Examp' 1B) in 200 ml. of dry pyridine is cooled to 0 C. an there is added a solution of 4 ml. of methanesulfon chloride in 20 ml. of chloroform. The mixture is kc at 0 C. for 3 hours, then the excess methanesulfon chloride is decomposed by the addition of a small amour of ice. The mixture is diluted with chloroform an washed with dilute hydrochloric acid and water. Tl organic solution is dried over magnesium sulfate, filters and evaporated in vacuo to a residue which is crystallize from acetone-ether to give 6a-methyl-l7a,2l-dihydrox: 4,9( 1 l )-pregnadiene-3,20-dione ZI-methanesulfonate.

D. 6a-METHYL-17a-HYDROXY-21-IOD0-4,9 11 -PREGNA DIENE3,20-DIONE A solution of 5 g. of the ZI-methanesulfonate of E: ample 1C in 50 ml. of acetone containing a few dro of pyridine is warmed slightly and there is added a wan solution of 10 g. of sodium iodide in 20 ml. of aceton The mixture is warmed on the steam bath for 5 minute then poured into cold water. A solid separates which filtered, washed with water and crystallized from acetoni hexane to give 6a-methyl-l7-hydroxy-21-iod0-4,9(l1: pregnadiene-3,20-dione.

EXAMPLE 2 oa-methyl-l7a-hydr0xy 2I-i0do-4.9(11 pregnadiene 3 ,20-di0ne 1 7-acerate A solution of l g. of 6a-methyl-l7a-hydroxy-21-iod 4,9(11)-pregnadiene-3,20-dione (the compound of E: ample l) in 20 ml. of acetic acid and 4 ml. of lllfillOl't acetic anhydride is allowed to stand at room temperatui for 16 hours and is then poured into ice water. A soli separates which is filtered, washed with water and cry:

:d from acetone-hexane to give Ga-methyI-I'Ia-hy- -2l-iodo-4,9( l l )-prcgnadiene-3,20-dione l7-acctate. nilarly, by substituting other lower alkanoic acids as propionic, butyric or valeric for acetic acid in bove procedure, the corresponding l7-esters are prel, i.e. the l7-propionate, 17-butyrate and 17-valerate, ctively of 6m methyl-17a-hydroxy-2l-iodo-4,9(ll)- ladiene-3,20-dione.

EXAMPLE 3 ia-methyl-9a,1 IB-dichloro-ZI Jada-1 7a-hydr oxyprogesterone I T-acetate One gram of 6a-methyl-17a-hydroxy-2Mode-4,9- -pregnadiene-3,20-dione l7-acetate (the compound of iple 2) is dissolved in 30 ml. of carbon tetrachloride iich is added at 20 C. a solution of 140 mg. of ine gas in 3 ml. of carbon tetrachloride and 0.2 ml. 'ridine. The mixture is stirred at -20 C. for 15 tes, then allowed to warm to room temperature: over hour period. The solution is filtered and the filtrate :ntrated in vacuo to a residue which upon trituration ether yields a solid which is crystallized from acehexane to give 6a-methyl-9a,1lp-dichloro-zl-iodo- \ydroxyprogesterone 17-acetate. t'ernatively, the compound of this example is prei according to the following procedures B and C. B. 6a-.\IETHYL-9a,1ldDICHLORO-21-IODO-17a- HYDROXYPROGESTERONE the manner described in Example 3A, one gram of ethyl 17a hydroxy-2l-iodo-4,9(l1)-pregnadiene- :lione (the compound of Example 1) is chlorinated 15 5 mg. of chlorine gas in carbon tetrachloride in the nce of 0.2 ml. of pyridine and the resultant product .cd and purified to give 6a-methyl-9a,llfi-dichlorodo-l7a-hydroxyprogesterone.

'.-METHYL-9d,11B-DICHLORO-ZI-IODOJ.TG-HYDROXY- PROGESTERO NE IT-ACETATE the manner described in Example 2, the l7a-hydroxy ogenated progesterone of Example 3B is reacted acetic acid and trifiuoroacetic anhydride and the reit product isolated and purified to give Git-methylllfl dichloro-Zl-iodo-17a-hydroxyprogesterone 17- te. i

a similar manner, by substituting other lower alkaacids such as propionic or butyric for acetic acid in bove procedure, the corresponding 17-esters are prel, i.e. 17-propionate and l7-butyrate of Gut-methylfi-dichloro-Z l -iodol 7a-hydroxyprogesterone.

EXAMPLE 4 1e grams of 6a-methyl l7a'- hydroxy 21 fluorol)-pregnadiene-3,20-dione is reacted with acetic acid rifiuoracetic anhydride according to the procedure of iple 2. The resultant product is isolated in the deed manner and crystallized from cetone-hexane to fiat-methyl 17a hydroxy-2l-fiuoro-4,9(l1)-pregna- :-3,20-dione l7-acetate.

EXAMPLE 5 methyl-1 7 a-h ydroxy-ZI -fluoro-4,9(1 1 )-pregnadiene- 3 ,ZO-dione 1 7-caproate mixture of l g. of a-methyl-l7a-hydroxy-2l-fiuorol) pregnadiene-3,20-dione and 5 ml. of caproic acid ated at 80 C. in the presence of 1 ml. of trifluoroanhydride for 45 minutes. The mixture is poured Ice water and the excess acid neutralized with sodium mate. The crude reaction mixture is extracted with ylene chloride. The organic extracts are combined :oncentrated to a residue which is chromatographed lorisil. The material eluatcd with 12-35% ether in 8 hexane is combined and crystallized from hexane to give 6a-methyl 17a hydroxy-21-fluoro-4,9(1l)-pregnadiene- 3,20-dione 17-caproate.

EXAMPLE 6 v 6e-methyl-9aJ IB-dichloro-ZI -fluoro-1 7a-hydroxyprogesterone 17-acetate A. A solution of l g. of 6a-methyl-17q-hydroxy-2l- 'fluoro-4,9(11)-pregnadiene 3,20 dione 17-acetate (the compound of Example 4)' and 4 g. of lithium chloride in 50 ml. of glacial acetic acid is cooled to about 10" C. and there is added 200 mg. of hydrogen chloride in 1 ml. of tetrahydrofuran followed by 340 mg. of N-chlorosuccinimide. The solution is stirred at room temperature for 20 minutes in the absence of light, then is poured into ice water with stirring. A precipitate forms which is filtered, washed with water, triturated with ether and crystallized from acetone-hexane to give 6z-methyl-9a,llfl-dichloro- 2l-fluoro-l7a-hydroxyprogesterone l7-acetate.

Alternatively, the compound of this example is prepared according to the following procedures B and C.

According to the procedure of Example 38, 6a-methyl- 17a-hydroxy-21-fluoro-4,9( l l )-pregnadiene-3,20-dione is chlorinated with chlorine gas in carbon tetrachloride in the presence of pyridine and the resultant product isolated and purified to give 6a-methyl-9qt,llB-dichloro-Zl-fiuoro- 17m-hydroxyprogesterone.

C. Oct-METHYL-QaJ1B-DICHLORO-21-FLUORO-17a-HY- DROXYPROGESTERONE l'l-ACETATE One gram of Ga-methyl-l7e-hydroxy-2l-fiuoro-4,9( l 1)- pregnadiene-3,20-dione l7-acetate (the compound of Example 4) and 790 mg. of p-iodotoluene dichloride are dissolved in 25 ml. of methylene chloride. The solution is stirred at room temperature for 5 hours, then concentrated in vacuo to a residue which is crystallized from acetone-hexane to give 60; mcthyl-9a,llfi-dichloro-Zlfluoro-l7a-hydroxyprogesterone l'l-acetate.

EXAMPLE 7- 6a-methyl-9a-bromo-I I S-chloro-ZI -flu0ro-1 7a-hydr0xyprogesterone 1 7-acetate A. One gram of 6c: methyl-l7a-hydroxy-21-fluoro- 4,9(11)-pregnadiene-3,20-dione l7-acetate (the compound of Example 4) and 4 g. of lithium chloride are dissolved in 40 ml. of glacial acetic acid. The solution is cooled to about 10 C. and there is added 250 mg. of hydrogen chloride in 1 ml. of tetrahydrofuran followed by 350 mg. of N-bromoacetamide. The solution is stirred at room temperature for 20 minutes in the absence of light, then is poured into ice water with stirring. A precipitate forms which is filtered, washed with water, triturated with ether and crystallized from acetone-hexane to give 6a-methyl- 17-acetate.

Alternatively, the compound of this example is prepared according to the following procedures B and C.

B. Ba-METHYL-Qa-BROMO-lIH-CHLORO-M-FLUORO- I'Ia-HYDROXYPROGESTERONE 6a methyl-lh-hydroxy-Zl-fluoro-4,9( 1 l )-pregnadiene 3,20-dione is reacted with N-bromoacetamide in the presence of hydrogen chloride and lithium chloride according to the procedure of Example 7A. The resultant product is isolated and purified in the described manner to give 60: methyl-9e-bromo-1lfi-chloro-Zl-fluoro-lh-hydroxyprogesterone.

C. 6a-METHYL-9a.-BROMO-11B-CHLOR0-21-FLUORO-17a- HYDROXYPROGESTERONE 17-ACETATE In the manner of Example 2, the l7m-hydroxyprogesterone of Example 7B is reacted with acetic acid and trifiuoroacetic anhydride to give 6amethyl-9e-bromo-llfichloro-Z l -fluoro-l 7a-hydroxyprogesterone 17-acetate.

In a similar manner, by substituting other lower alkanoic acids such as butyric and Valerie for acetic acid in the above procedure, the corresponding l7-esters are obtained, i.e. the 17 -butyrate and 17 -'valerate of 6amethyl 9e bromo 11B chloro-2l-fluoro-l7a-hydroxyprogesterone.

EXAMPLE 8 6 a-meth yI-9a-bromo-1 1 5,21 -difluro-1 7u-hydroxyprogesterone I 7-acetate A. 500 mg. of 6a methyl 17a hydroxy-Zl-fiuoro- 4,9(1l)-pregnadiene-3,20-dione l7-acetate (the compound of Example 4) is dissolved in 25 ml. of diethylacetic acid and there is added a solution of 600 mg. of hydrogen fluoride in 2.5 ml. of a chloroform-tetrahydrofuran mixture followed by. 175 mg. of N-bromoacetamide. The solution is stirred at room temperature for 1% hours, poured into potassium carbonate solution with vigorous stirring, then is extracted with methylene chloride. The organic extracts are combined, washed with 5% sodium hydroxide in water, dried over magnesium sulfate, filtered and concentrated to a residue which is crystallized from methylene-chloride-hexane to give 6a-methyl9a-brom0- 1 1,8,2l-difiuoro-l7a-hydroxyprogesterone 17-acetate.

Alternatively, the compound of this example is pre pared according to the following procedures B and C.

B. 6a-METHYL-9a-BROMO-11B,21-DIFLUORO-17a- HYDROXYPROGESTERONE 6o: methyl-17a hydroxy-21-fiuoro-4,9(ll) pregnadiene-3,20-dione is reacted with N-bromoacetamide and hydrogen fluoride according to the procedure of Example 8A. The resultant product is isolated and purified in the described manner to give 6a-methyl-9a-bromo-l13,21- difiuoro-l7a-hydroxyprogesterone.

c. 6a-METHYLQa-BRoMo-ne,21-DIFLUORo-17a- HYDROXYPROGESTERONE 17-ACETATE The l7a-hydroxyprogesterone of Example 8B is esterified by means of acetic acid and trifiuoroacetic anhydride in the manner described in Example 2 to give 6a-methyl- 9a-bl0l'll0 l15,2l-difiuoro-l7e-hydroxyprogesterone 17- acetate.

EXAMPLE 9 A. 500 mg. of fiat-methyl-l7e-hydroxy-2l-fluoro-4,9- (ll)-pregnadiene-3,20-dione 17-acetate (the compound of Example 4) is dissolved in 20 ml. of acetic acid and there is added 285 mg. of N-iodosuccinimide and a solution of 49 mg. of hydrogen chloride in 1.7 ml. of tetrahydrofuran followed by 2 g. of lithium chloride. The mixture is stirred at room temperature for 20 minutes, then poured into water and extracted with methylene chloride. The organic extracts are washed with dilute aqueous sodium bicarbonate solution and then with water. The solution is dried over magnesium sulfate, filtered and concentrated in vacuo to a residue which is triturated with ether and crystallized from acetone-hexane to give 6a-rnethyl-9a- 10 iodo-llfl-chloro-M-fiuoro l7a-hydroxyprogesterone 1 acetate.

Alternatively, the compound of this example is p1 pared according to the following procedures B and C.

B. Ba-METHYL-9e-IOD0-11n-CHLORo-21-FLUORO-17a- HYDROXYPROGESTERONE 6a methyl l7a-hydroxy 21 fiuoro-4,9(1l)-pre nadiene-3,20-dione is reacted with N-iodosuccinimide a1 hydrogen chloride in the presence of lithium chloride 2 cording to the procedure of Example 9A. The results product is isolated and purified in the described mann to give 60: methyl 9a-iodo-1lfl-chloro-2l-fluoro-17a-h droxyprogesterone.

C. Git-METHYL-9a-IODO-11B-CHI10R0-21-FLUORO-17a- HYDROXYPROGESTERONE 17-ACETATE The l7a-hydroxyprogesterone of Example 98 is este fied by means of acetic acid and trifluoroacetic anhydri in the manner described in Example 2 to give 6a-meth1 9a iodo-llfi chloro-Zl-fluoro-17a-hydroxyprogestero 17-acetate.

Similarly, 'by substituting other lower alkanoic aci acids such as propionic and butyric for acetic acid in t above procedure the corresponding l7-esters are obtain: i.e. the 17-propionate and l7-butyrate'of 6a-methyl-9 iodo-l lfl-chloro-Zl -fiuoro-17m-hydroxyprogesterone.

EXAMPLE 10 6ix-methyl-9aJ 1 B-dich lore-21 -flu0r0-1 7ahydroxyprogesterone 17-capr0ate One gram of 6a-methyl-l7a-hydroxy-2l-fluoro-4,9( ll pregnadiene-3,20-dione 17-caproate (the compound Example 5) is reacted with 300 mg. of N-chloros1 cinimide and 200 mg. of hydrogen chloride in the preset: of lithium chloride according to the procedure of E ample 6. The resultant product is isolated in the t scribed manner and'crystallized from acetone-hexane give 60: methyl 9u,1 1p-dichloro-2l-fluoro-l7a-hydrol progesterone 17-caproate.

EXAMPLE i1 6a-methyl-9a-bromo-l15,21-difluoro-1 7 ahydroxyprogesterone 1 7-capr0ate 500 mg. of 6a-methyl-17a-hydroxy-21-fiuoro-4,9(l1 pregnadiene-3,20-dione l7-caproate (the compound of I ample 5) is reacted with mg. of N-bromoacetami and 600 mg. of hydrogen fluoride in the manner descril: in Example 8. The resultant product is isolated and pu fied in the described manner to give 6a-methyl-9a-bron 1l 3,2l-difluoro-l7a-hydroxyprogesterone l7-caproate.

EXAMPLE 12 Got-I 7a-dimethyl-4,9(I1 )-pregnadiene-3,20-dione A. 17a-METHYLPROGESTERONE 3,20-BISETHYLENB KETAL To a solution of 20 g. of the bisethylene ketal of l ample 12A in 320 ml. of chloroform containing 4 (111 of pyridine is added with a solution of 14.7 g. of mm perphthalic acid in 200 ml. of ether at 0 C. The m ture is allowed to stand at 0 C. for 24 hours, tl

ed with ether and washed three times with'5% aquebicarbonate and twice with water. The solution is l over magnesium sulfate, fil':ered and the solvent re- :d in vacuo. The resultant residue is chromatohed on Florisil in hexane. The column is first eluted 20-40% ether in hexane to separate the 5,8,65- ide of l7a-methylpregnane-3,20-dione 3,20-bisethylketal from the desired product. The column is then d with 100% ether and 1% acetone in ether, and :luates concentrated in vacuo to a residue which is allized from acetone-hexane to give a,6m-epoxy-l7atylpregnane-3,20-dione 3,20-hisethylene ketal.

1e Seems-epoxy of Example 12B g.) in 200 ml. :trahydrofuran and 200 ml. of benzene is added to ignard reagent prepared from 5 g. of magnesium and 11. of methyl iodide in 200 ml. of ether. The ether istilledoil? and the reaction mixture is refluxed 19 hours. The mixture is chilled and an aqueammonium chloride solution added, The sollayers are separated and the organic layer washed water and concentrated. The resultant residue is lved in 200 ml. of 90% aqueous methanol, refluxed 3 g. of oxalic acid for 30 minutes, then poured into r. A solid forms which is filtered and crystallized acetone-hexane to give 5a-hydroxy-6fi',l7a-dimethyluane-3,20-dione.

D. 6a,IIa-DIMETHYLPROGESTERONE vo grams of 5a-hydroxy-6fl,l7a-dimethylpregnanedione (the compound of Example 12C) in 150 ml. of sol containing 0.5 ml. of concentrated hydrochloric is refluxed for 30 minutes. The solution is then ed into water, the resultant solid filtered, and crystalfrom aqueous methanol to give 6a,l7a-dimethylesterone.

6a,].7tI-DIMETHYL-1IB-HYDROXYPROGESTERONE 0 ml. of this medium is placed in each of several ml. flasks. To each flask is added 50 mg. of 601,170:- :thylprogesterone (the compound of Example 12D) lived in a small volume of acetone. The mixture taken for a period of 7 days at a room temperature bout 28 C. The contents of the flasks are then com- :1 and extracted with several portions of ethylene diride using one-fifth the volume of the aqueous phase time. The combined organic extracts are dried over an sulfate, filtered and concentrated in vacuo to a lue having a volume of l2 ml. 1e ethylene dichloride residue is then placed on a matographic column consisting of silica gel, mixed at small volume of methylene chloride. The colis developed with methylene chloride and the eluates combined and concentrated in vacuo to a residue h is crystallized from acetone-hexane to give 6,17a- :thyl-l l p-hydroxyprogesterone.

F. 6:1,17 a-DIMETHYL4,9 (11 -PREGNADIENE- 3.20-DIONE t,17-dimethyl1lp-hydroxyprogesterone (the comcompound of Example 12B) is reacted with methanesul- EXAMPLE l3 6a,]7a-dimethyl-2I-iodo-4.9(11)-pregnadiene- 3,20-dione To a solution of 10 g. of 6,17a-dimethyl-4,9(ll)- pregnadiene-Il,20-dione (the compound of Example 12) in 75 ml. of tetrahydrofuran and 40 ml. of methanol is added 17.5 g. of iodine and 17.5 g. of finely powdered calcium oxide. The mixture is stirred at room temperature for 3 hours, then poured into 1.5 l. of cold water containing 60 ml. of acetic acid. The mixture is extracted wtih methylene chloride and the organic extracts are washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo to a residue which is crystallized' from methylene chloridehexane to give 6a,l7a-dimethyl-2l-iodo-4,9(ll)-pregnadiene-3,20-dione.

' EXAMPLE l4 7 6a,] 7a-dim eth yl-9a,1 I B-dichloro-2l' -iodoprogesterone One gram or 6a,17a-dimethyl-21-iodo-4,9(11)-pregnadiene-3,20-dione (the compound of Example 13) is reacted with mg. of chlorine in carbon tetrachloride in the manner described in Example 3A. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 6u,17a-dimethyl-9, l 1,6-dichloro-21-iodoprogesterone.

EXAMPLE 15 6a,] 7a-dimethyl-2I -fluor0-4,9( 1 I )-pregnadiene- 3,20-dione EXAMPLE 16 6a,I7a-dimethyl-9,1Ip-dichIOro-ZI-flu0ropr0gesterone One gram of 6a,17e-dimethy1-21-tluoro-4,9(1l)-pregnadiene-3,20-dione (the compound of Example 15) is f reacted with 380 mg. of N-chlorosuccinimide in the presence of hydrogen chloride and lithium chloride according to the procedure of Example 6. The resultant prod uct is-isolated in the described manner and crystallized from acetone-hexane to give 6,l7a-dimcthyl-9,l1fldichloro-2l-fluoroprogesterone.

EXAMPLE 17 6a,] 7a-dimethyl-9m-chloro-l13,21-difluoropr0gestcrone 1 I 500 mg. of 6a,l7a-dimethyl-2l-fluoro-4,9(l1)-pregnadiene-3,20-dione (the compound of Example 15) is dissolved in 25 ml. of diethylacetic acid and there is added mg. of N-chlorosuccinimide followed by a solution of 775 mg. of hydrogen fluoride in 4 ml. of a mixture of tetrahydrofuran in chloroform. The reaction mixture is stirred at room temperature for 48 hours, then is poured into an aqueous sodium carbonate solution and extracted with methylene chloride. The organic extracts are combined and evaporated to a residue which is chromatographed on Florisil. The product eluted with 20-40% ether in hexane is combined and recrystallized from methylene chloride-hexane to give 6a,l7a-dimethyl-9uchloro-l 1p,21-difluoroprogesterone.

13 EXAMPLE 1:;

500 mg. of 6a,17a-dimethyl-2l-fiuoro-4,9(ll)-pregnadiene-3,20-dione (the compound of Example 15) and 2 g. of lithium bromide are dissolved in 25 ml. of acetic acid. 200 mg. of N-bromoacetamide are added followed by a solution of 125 mg. of hydrogen bromide in 2 ml. of acetic acid. The mixture is stirred at room temperature for 1 hour, then poured into ice water. A solid precipitates which is filtered, washed with water and crystallized from methylene chloride-pentane to give 6e,17a dimethyl 9a,11fi dibromo 21 e fluoroprogesterone.

EXAMPLE 19 6a-methyl-17a-brom0-4,9 (I1 -pregnadiene-3,20-dione A. ITa-BROMOPROGESTERONE 3,20-BISETHYLENE KETAL 30 g. of 17a-bromoprogesterone is reacted with 400 ml. of ethylene glycol in the presence of p-toluenesulfonic acid according to the procedure of Example 12A. The resultant product is isolated in the described manner and crystallized from acetone-ether to give 17a-bromoprogesterone 3,20-bisethylene ketal.

B. a,6a'EPOXY-17a-BROMOPREGNANE-3,20-DIONE 3,20-BISETHYLENE KETAL Five grams of the 'bisethylene ketal prepared in Example 19A is reacted with monophthalic acid according to the procedure of Example 128 and the resultant product isolated and purified to give 5a,6a-epoxy-l7a-bromopregnane-3,20-dione 3,20-bisethylene ketal.

C. SQ-HYDROXY-GB-METHYL-I7aBROMOPREGNANE- 3,20-DIONE Five grams of the 5a,6a-epoxy bisethylene ketal of Example 198 is reacted with methyl magnesium iodide followed by treatment with oxalic acid and the resultant product isolated in the manner described in Example 120. The isolated product is crystallized from acetone-hexane to give 5a-hydroxy-6fl-methyl-17-bromopregnane-3,20- dione.

D. (So-METHYIrI'Ia-BROMOPROGESTERONE Two grams of swhydroxy-6p-methyl-l7a-bromopregnane-3,20-dione (the compound of Example 19C) is dissolved in 150 ml. of ethanol containing 0.5 ml. of concentrated hydrochloric acid. The solution is refluxed for 30 minutes, then cooled and poured into water. A solid separates which is filtered and crystallized from aqueous methanol to give 6a-methyl-l7e-bromoprogesterone.

E. Ba-METHYL-llfi-HYDROXY-l 7a-BROMOPRO- GESTERONE In the manner described in Example 12E, 4 g. of 6amethyl-l7a-bromoprogesterone (the compound of Example 19D) is subjected to the action of a culture of the microorganism Curvularia humid and the resulatnt product isolated and purified to give fiat-methyl-llfl-hydroxy-l7a-bromoprogesterone.

F. 6e-METHYL-17a-BROMO-4.9 (11 )-PREGNADIENE- 3,20-DIONE Two grams of Ga-methyl-llp-hydroxy-lh-bromo-- progesterone (the compound of Example 19E) is refluxed for 30 minutes with a solution of 4 g. of dry lithium bromide in 50 ml. of glacial acetic acid. The solution is poured into water and the resultant solid is filtered,

washed withwater and crystallized from acetone-hexane to give 6a-methyl-17a-bromo-4,9( 1 1)-pregnadiene-3,20- dione. F

14 EXAMPLE :0

6 a-methyl-I 7a-bromo-2I -fluoro-4,9 (I I -pregnadiene- 3,20-dione A. 6aME'rHYL-17a-BROM0-21-IOD04,9(In-PREGNA- DIENE-3,20-DIONE EXAMPLE 21 6 a-methyl-9a,1 I fl-dich loro-I 7at-bromo-21-flu0roprogesterone One gram of 6a-methyl-17a-brom0-2l-flu0ro-4,9( l1 pregnadiene-3,20-dione (the compound of Example 2( is reacted with 330 mg. of N-ehlorosuccinimide in t1 presence of hydrogen chloride and lithium chloride in tl manner of Example 6. The resultant product is isolate in the described manner and crystallized from aceton hexane to give 6a-methyl-9a,1lfl-dichloro-lh-bromo-Z fluoroprogesterone.

. EXAMPLE 22 500 mg. of 6a-methyl-l7a-bromo-2l-fiuoro-4,9(ll prcgnadiene-3,20-dione (the compound of Example. 2( is reacted with mg. of N-bromoacetamide in the pre ence of hydrogen chloride and lithium chloride in tl manner described in Example 7. The resultant produ is isolated in the described manner and crystallized fro; acetone-hexane to give 6a-methyl-9e,l7a-dibromo-lI chloro-Zl-fluoroprogesterone.

EXAMPLE 23 6a-fluoro-21-iodo-I 7a-hydr0xy-4,9(1 I -pregnadiene- 3,20-di0ne A. 6a-FLUORO-17a.21-DIHYDROXY-4,9 (11 -PREGNA- DIENE-3,20-DIO NE 21-METHANESULFONATE Ten grams of 6a-fluoro-17u,2l-dihydroxy-4,9(ll pregnadiene-3,20-dione is reacted with 4 ml. of methan sulfonyl chloride in the manner described in Example It The resultant product is isolated in the described mannt and crystallized from acetone-ether to give 6a-fluoro-l7 21 dih-ydroxy 4,9( l1)-pregnadiene-3,20-dione 2l-metl anesulfonate.

B. 6a-FLUOR0-21-IOD0-17a-HYDROXY-4,9 (11) -PREGNA DIENE-3,20-DIONE Eight grams of the ZI-methanesulfonate of Examp 23A is reacted with sodium iodide in the manner d scribed in Example 1D and the resultant product isolate and purified to give 6-fluoro2l-iodo-l7a-hydroxy- 9(ll)-pregnadiene-3,20-dione.

EXAMPLE 24 6a-fluor0-2I-iodo-]7a-hydroxy-4,9(II)-pregnadiene- 3,20-dione I 7-acetate 1.5 g. of 6a-fluoro-21-iodo-17u-hydroxy-4,9(l1)-pre nadiene-3,20-dione (the compound of Example 23) reacted with acetic acid and trifluoroacetic anhydride i the manner described in Example 2. The resultant prot uct is isolated and purified to give 6a-fluoro-2l-iodo-l7 hydroxy-4,9(1 l)-pregnadiene-3,20-dione l7-acetate.

15 EXAMPLE 2s 6a-flu0ro-9aJ I fl-dich lam-21 Jada-1 7a-hydroxyprogesterone 1 7 -aceta te One gram of 6at-fluoro-2l-iodo-l7et-hydroxy-4, )-pregnadiene 3,20-dione l7-acetate (the compound sample 24) is reacted with 140 mg. of chlorine in in tetrachloride in the manner described in Example The resultant product is isolated in the described ter and crystallized from acetone-hexane to give 6::- J 9,llfl dichloro 21 iodo 17a hydroxypro- TOHC 17-acetate.

ternatively, the compound of this example is prel according to the following procedures B and C.

B. 6G'FLUOR0-9fl,11B-DICHLoR0-21 -IODO17a.- HYDROXYPROGESTERONE e gram of 6a-fluoro-2l-iodo-l7a-hydroxy-4,9(l1)- ladiene-3,20-dione (prepared as in Example 23) is ad with chlorine in carbon tetrachloride and the re 1t product isolated and purified in the manner de- :d in Example 38 to give 6a-fiuoro-9a,llfl-dichlorodo-l7a-hydroxyprogesterone.

z-FLUORO -9a,11B-DICHLORO-21-IODO-1Ta-HYDROXY- PROGESTERONE IT-ACETATE the manner described in Example 2, the lla-hytprogesterone of Example 25B is esterified by means :etic acid and trifiuoroacetic anhydride to give 60:- 901,115 dichloro 21 iodo 17a hydroxyprorone l'l-acetate.

a similar manner, by substituting other lower lOlC acids such as propionic and butyric for acetic in the above procedure the corresponding l7-lower toates are prepared, i.e. the l7-propionate and 17- am, respectively of 6a-fiuoro-9a,11fl-dichloro-21- 'l 7 a-hydroxyprogesterone.

EXAMPLE 26 541,21 -difluro-1 7 a-hydroxy-4,9 1 1 )-pregnadiene- 3,20-di0ne ve grams of 6a-fiuoro-2l-iodo-l7e-hydroxy-4,9(l1)- iadiene-3,20-dione (the compound of Example 23) acted with 1.3 g. of silver fiuoride and the resultant uce isolated and purified in the manner described in nple 15 to give 6 a,2l-difiuoro-17a-hydroxy-4,9(11)- iadieue-3,20-dione.

EXAMPLE 27 ,21 -difluoro-I 7ut-hydroxy4,9( 1 I -pregnadiene-3,20-

dione 17-acetate the manner described in Example 2, the l7a-hyypregnadiene of Example 26 is reacted with acetic and trifiuoroacetic anhydride and the resultant prodisolated and purified to give 6a,2l-ditluoro-l7a-hyy-4,9( l 1 )-pregnadiene-3,20-dione 17-acetate.

EXAMPLE 28 ,21 -diflu0ro-1 7a-hydr0xy-4,9(11 -pregnadiene-3,20-

dione 1 7 -capr0ate g. of the 17a-hydroxypregnadiene of Example 26 terified by means of caproic acid and trifluoroacetic 'dride in the manner described in Example 5. The .tant product is isolated and purified in the described ner to give 6,2l-difluoro-l7a-hydroxy-4,9(l1)- nadiene-3,20-dione 17-caproate.

similar manner, by substituting other lower alkanoic l for caproic acid such as valeric and propionic in the 'e procedure, the corresponding 17-esters are ob- :d, i.e. l7-valerate and 17-propionate, respectively, 50:,2 l-difluoro-17a-hydroxy-4,9( l 1 -pregnadiene-3,20-

e. I I i 1 6 EXAMPLE 29 A. One gram of 61,2l-difiuoro-lh-hydroxy-4,9(l1)- pregnadiene-3,20-dione l7-acetate (the compound of Example 27) is reacted with 340mg. of N-chlorosuccinimide in the presence of hydrogen chloride and lithium chloride in the manner described in Example 6. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 6a,2l-difluor0- 9a,1lfi-dichloro-17a-hydroxyprogesterone l7-acetate.

Alternatively, the compound of this example is prepared according to the following procedures B and C.

B. 60.,21 -DIFLUORO-9a,11fl-DICHLORO-17d- HYDROXYPROGESTEBONE One gram or 6a,2l-difluoro-17a-hydr0xy-4,9(1l)-prcgnadiene-3,20-dione (the compound of Example 26) is chlorinated with chlorine gas in carbon tetrachloride in the manner of Example 3B. The resultant product is isolated and purified in the described manner to give 6a,21- difiuoro-9m, l lp-dichloro-l 7a-hydroxyprogesterone.

C. 6a,21-DIFLUORO-9a,l1fl-DICHLOR0-17a-HYDROXY- PROGESTERONE l'l-ACETATE The l7a-hydroxyprogesterone of Example 293 is esterified by means of acetic acid and trifiuoroacetic anhydride in the manner described in Example 2 to give 6a,21-difluoro 9a,l lB-dichlortrl7a-hydroxyprogesterone l7-acetate.

Similarly, by substituting other lower alkanoic acids such as propionic and butyric for acetic acid in the above procedure, the corresponding l7-esters are obtained, i.e. the l'l-propionate and l7-butyrate of 6a,2l-difluoro-9a.- 1 lp-dichloro-l 7a-hydroxyprogesterone.

EXAMPLE 30 6 (1,1 1 5,21 drifluoro-Qa-broMO-I 7e-hydroxyprogesterone 1 7-acetate A. One gram of 611,21-difiuoro-l7a-hydroxy-4,9(ll)- pregnadiene-3,20-dione 17-acetate (the compound of Example 27) is reacted with 350 mg. of N-bromoacetamide and hydrogen fluoride in the manner described in Example 8A. The resultant product is isolated in the described manner and crystallized from methylene chloridehexane to give 6a,l13,21-trifluoro-9a-bromo-17a-hydroxyprogesterone l7-acetate.

' Alternatively, the compound of this example is prepared according to the following procedures B and C.

3. 60,11 B,21-TRIFLUORO-9a-BROMO-17c- HYDROXYPROGESTERON E 60:,21 difluoro-17a-hydroxy-4,9(1 l -pregnadiene-3,20- dione (the compound of Example 26) is reacted with N-bromoacetamide and hydrogen fluoride in the manner described in Example 88 and the resultant product isolated and purified to give 6a,llfl,2l-trifluoro-9a-bromo- 17a-hydroxyprogesterone.

C. 6a.,115,21-TRIFLUORO-9a'BROMO-1Ta-HYDROXY- PROGESTERONE 17-ACETATE EXAMPLE 31 6a,21 difiuoro-17m-hydroxy-4,9(11)-pregnadiene-3,20- dione (the compound of Example 26) is reacted with N-iodosuccinimide in the presence of hydrogen chloride and lithium chloride in the manner described in Example 9B. The resultant product is isolated and purified in the described manner to give 60:,21-difil101'O-9a-iOdO-l1fichlorol7a-hydroxyprogesterone.

C. 6a.,21 -DIFLUORO-Qa-IODO-lIfl-CHIJO RO-l Ta-HYDROXY- PROGESTERONE I'I-ACETATE In the manner described in Example 2, the 17a-hydroxyprogesterone of Example 31B is esterified by means of acetic acid and triiluoroacetic anhydride to give 6u,2ldifiuoro-9a-iodo-l lp-chloro-17a-hydroxyprogesterone 17- acetate.

In similar manner, by substituting other lower alkanoie acids such as n-butyric and propionic acid for acetic acid in the above procedure, the corresponding 17-1ower alkanoates are obtained, i.e. the I7-n-butyrate and l7-propionate of 6a,21-difiuoro-9a-iodo-11fl-chloro-17a-hydroxyprogesterone.

EXAMPLE 32 6a,21 -difluro-9a,1 1 fl-dichloro-I 7a-hydroxyprogesterone 1 7 -capr0ate One gram of 6a,2l-difiuoro-l7a-hydroxy-4,9(l1)-pregnadiene-3,20-dione 17-caproate (the compound of Example 28) is reacted with 300 mg. of N-chlorosuccinimide in the presence of hydrogen chloride and lithium chloride in the manner described in Example 6. The resultant product is isolated in the described manner and crystallized from ether to give 6a,2l-difluoro-9a,llfi-dichloro l7a-hydroxyprogesterone 17-caproate.

EXAMPLE 33 To g. of 5a,6a-epoxy-l7a-methylpregnane-3,20-dione 3,20-bisethylene ketal (the compound of Example 128) in 100 ml. of methylene chloride is added 5 ml. of 48% hydrofluoric acid. The mixture is stirred for 6 hours, then washed with water and concentrated to a residue. The residue is dissolved in 60 ml. of methanol and refluxed with 2 ml. of 1 N-sulfuric acid for 30 minutes. The solution is diluted with water and extracted with methylene chloride. The extract is washed with water, dried over magnesium sulfate, filtered and evaporated to a residue which is chromatographed on Florisil. The fractions eluated with 60l00% ether in hexane are combined and evaporated to a residue which is crystallized from acetone-hexane to give 5a-hydroxy-6B-fluoro 17a-methylpregnane-3,20-dione.

B. 6a-FLUOR0-17a-METHYLPROGESTERONE Two grams of 5a-hydroxy-6B-fiuoro-17a-methylpregnane-3,20-dione (the compound of Example 33A) in 150 ml. of ethanol containing 0.5 ml. of concentrated 18 hydrochloric acid is refluxed for 30 minutes. The solution is then poured into water. The resultant solid is filtered and crystallized from aqueous methanol to give 6a-fiuoro-17a-methylprogesterone.

c. Ga-FLUORO-l1B-HYDROXY-I7a-METHYLPRO- GESTERONE 6a-fiuor0-17a-methylprogesterone (the compound of Example 33B) is subjected to the action of a culture of the microorganism Curvularia lunata in the manner described in Example 12E. The resultant product is isolated and purified in the described manner to give 6a-fluorol 1 B-hydroxyl7a-methylprogwterone.

D. Ba-FLUORO-l 7a-METHYL-4,9 (11 -PREGNADIENE- 3,20-DIONE In the manner described in Example 1A, 6a-fluoro-l1flhydroxy-l7a-methylprogesterone (the compound of Example 33C) is reacted with methane-sulfonyl chloride in dimethylformamide-pyridine and the resultant product isolated and purified to give 6a-fiuoro-17a-methyl-4,9(11)- pregnadiene-3,20- dione.

E. 6a-FLUORO-21-IODO-1'(n-METHYL-LQ(11)PREGNA- DIENE-Ii,20-DIONE In the manner described in Example 13, 6a-fiu0t'Q-17amethyl-4,9(1l)-pregnadiene-3,20-dione (the compound of Example 33D) is reacted with iodine and calcium oxide and the resultant product isolated and purified to give 6:: fluoro-2l-iodo-l7a-methyl-4,9( 1 1 )-pregnadiene-3,20- dione.

EXAMPLE 34 In the manner described in Example 3, l g. of 6afiuoro-2l-iodo-l7a-methyl 4,9(11) pregnadiene 3,20- dione (the compound of Example 33) is reacted with mg. of chlorine gas in carbon tetrachloride and in the presence of pyridine. The resultant-product is ism lated and purified in the described manner to give 61:.- fluoro-9a,l lfl-dichloro-Z1-iodo-l7a-methyl-progesterone.

EXAMPLE 35 6:1,21-difluoro-17a-methyl-4,9(11 )-pregnadiene- 3,20-di0ne Five grams of 6a-fiuoro-2l-iodo-l7a-methyl-4,9(l1)- pregnadiene-3,20-dione (the compound of Example 33) is reacted with 1.4 g. of silver fluoride in the manner de scribed in Example 15. The resultant product is isolated in the described manner and crystallized from acetonehexane to give 6a,2l-difluoro-l7a-methyl-4,9(l1)-pregnadiene-3,20-dione.

EXAMPLE 36 611,21 -difluoro-9a1 1 BdichIoro-I 7u-methylprogesterone One gram of 60121 difluoro 17oz methyl -4,9(l1)- pregnadiene-3,20-dione (the compound of Example 35) is reacted with 380 mg. of N-chlorosuccinimide in the presence of hydrogen chloride and lithium chloride according to the procedure described in Example 6. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 6a,2l-difluoro- 9a,1 lfi-dichlorol 7a-methylprogesterone.

EXAMPLE 37 611,21 -difluor0-9a-br0m 0-1 I B-chloro-I 7a-methyl progesterone One gram of 6a,2l-difluoro-l7a-methyl-4,9(l1)-pregnadiene-3,20-dione (the compound of Example 35) is reacted with 390 mg. of N-bromacetamide in the presence of hydrogen chloride and lithium chloride in the manner described in Example 7. The resultant product is isolated in the described manner and crystall-ized from acetone-ether to give 6a,2l-difiuoro-9a-bromo-l lfi-chloro- 17a-methylprogesterone.

19 EXAMPLE 3:;

A. lid-HYDROXY-fifi-FLUORO-17a-BROMOPREGNANE- 3,20-DIONE Five grams of 5a,6a-epoxy-17a-bromopregnane-3,20- one, 3,20-bisethylene ketal (the compound of Example B) is reacted with hydrofluoric acid in methylene lor-ide according to the procedure of Example 120. me resultant product is isolated and purified in the deribed manner to give 5e-hydroxy-6fl-fluoro-l7a-bromoegnane-3,20-dione.

B. 6a-FLUORO-l'ia-BROMOPROGESTERONE The 5a-hydroxy-6p-fiuoropregnane of Example 38A is :hydrated with hydrochloric acid in the manner deribed in Example 12D. The resultant product is isoted in the described manner and crystallized from ueous methanol to give 6a-fluoro-17u-bromoprogesrone.

c. (Sc-FLUORO-HwBROMO-11fi-HYDROXYPROGES- TERONE Three grams of oat-fluorol7a-bromoprogesterone (pretred as described in Example 388) is subjected to the :tion of a culture of the microorganism Curvularia :nata in the manner described in Example 12E. The :sultant product is isolated and purified in the described .anner to give 6a-fluoro-17e-bromo-l lfi-hydroxypro- :sterone.

D. 6a-FLUORO-1 Ta-BROMO 4,9 (11)-PREGNADIENE- 3,20DIONE 6c: fluoro 17a-bromo-l lfl-hydroxyprogesterone (the mpound of Example 38C) is dehydrated with lithium romide in glacial acetic acid in the manner described l Example 19F. The resultant product is isolated in the ascribed manner and crystallized from acetone-hexane I give 6:: fluoro-l7a-bromo-4,9(1l)-pregnadiene-3,20 ione.

EXAMPLE 39 6 (1,21 -difluora-1 7 a-br0m0-4,9( 1 1 )-pregnadiene-3,20-

dione A. 6a.-FLUORO17e-BROMO-21-IOD0-4,9 (11 -PR.EGNA- DIENEl-3,20-DIONE Two grams of 6a-fiuoro-l7a-brorno-4,9(ll)-pregnaiene-3,20-dione (the compound of Example 38) is re cted with iodine and calcium oxide in the manner of ixample 3. The resultant product is isolated and puried in the described manner to give 6a-fluoro-17abromol-iodo-4,9( 1 1 -pregnadiene-3,20-dione.

B. 6a,21-D1FLUOR0-17a-BROMO-4,9 (1 1 -PREGNADIENE- 3,20-mom:

The 21-iodopregnadiene of Example 39A is reacted with silver fluoride in the manner described in Example 5. The resultant product is isolated in the described nanner and crystallized from acetone-hexane to give ie,2l-difluoro-17u bromo 4,9(11) pregnadiene 3,20- lione.

EXAMPLE 40 6a,21 -difl0ra-1 911,11 ,B-dichloro-I 7 a-bramopragesterone ample 39) and 785 mg. of p-iodotoluene dichloride are dissolved in 25 ml. of methylene chloride. The solution EXAMPLE 41 6 a-methyl-I 7a-hydr0xy-21-iodo-1 ,4 ,9(1 1 -pregna1riene- 3,20-dione Five grams of 6a-methyl-17a-hydroxy-21-iodo-4,9(1 l)- pregnadiene-3,20 lione is fermented with Corynebacterium simplex (A.T.C.C. 6946) according to the procedure of US. Patent No. 2,837,464 as follows.

A ml. broth culture containing a 0.1% yeast extract concentration, 9.0 ml. of 0.2 M KH PO and 9.0 ml. of 0.2 M Na HPO contained in a 300 ml. Erlenmeyer flask, is seeded with 1 m1. of a 24-hour broth culture of Corynebacterium simplex. The flask is'incub-ated at 28 C. for 24 hours. A second 300 ml. Erlenmeyer flask containing mg. of sterile 6a-methyl-17a-hydroxy-2l-icdo- 4,9(11)-pregnadiene-3,20-dione (the compound of E1 ample 1) in 5.0 ml. of acetone is inoculated with the 24- hour culture of Corynebacterium simplex. The culturecontaining steroid solution is incubated for 48 hours at 28 to 30 C.

After termination of the transformation period, the pH is 7.2-7.3. The culture is now directly extracted with 3 equal volumes of CHCI the solvent volumes combined and concentrated on a steam bath to a residue which is crystallized from acetone-hexane to give dot-methyl- 17e-hydroxy 21-iod0-1,4,9( l 1 -pregnatriene-3 ,ZO-dione.

Similarly, by subjecting to the action of a culture of the microorganism Corynebacterium simplex in the manner described above, the 4,9(l1)-pregnadiene intermediates prepared in the above examples are converted to their respective M-dehydro analogs, namely: 6a-methyl-l7ehydroxy-Zl-ioclo-1,4,9( 1 1 )-pregnatriene 3,20 dione 17- acetate, 6e-methyl-l7a hydroxy 21 fluoro 1,4,9(11)- pregnatriene-3,20-di0ne 17-acetate, 6a methyl 17 hydroxy 21 fluoro 1,4,9(11) pregnatriene 3,20 dione l7-caproate, Gun-17a. dimethyl 1,4,9( 11) pregrratriene- 3,20-dione, 6a,l7e-dirnethyl-2l-iodo 1,4,9( 11) pregnatriene-3,20-dione, 16:1,17a-dimethyl-2l-fluoro l,4,9( 1 l pregnatriene-3,20-dione, 6a-methyl-17e-bromo-1,4,9( l 1 pregnatriene-3,20-dione, 6a-methyl-l7a-bromo-2l iodo 1,4,9(1 l)-pregnatriene-3,20-dione, 6a-methyl-l7a-bromo- 21-fluoro-1,4,9( 1 l )-pregnatriene-3,20-dione, 6a-fiuoro-2liodo-l7a-hydroxy-1,4,9(11-) pregnatriene 3,20 dione, 6a-fluoro-2l-iodo-17e-hydroxy 1,4,9(11) pregnatriene- 3,20 dione 17 acetate, 6a,2l difluoro 17m hydroxyl,4,9(1 1)-pregnatriene-3,20 dione, 60;,21 difluoro 17ahydroxy-l,4,9(l1) pregnatriene 3,20 dione l7-acetate, 6a,2l difluoro 17 hydroxy 1,4,9(i1) pregnatn'ene- 3,20-dione 17-caproate, Got-fillOI'O-Zl-iOdO 17a methyl- 1,4,9( 11 )-pregnatriene-3,20-dione, 611-21 difluoro 17amethyl 1,4,9(11) pregnatriene 3,20 dione, 6a-fiuoro- 17-bromo-l,4,9( l 1 -pregnatriene-3,20-dione, Get-fluorol7u-brOm02l-iOdO-l,4,9(ll) pregnatriene 3,20-dione, and 6a,2l-difluOt0-17a bromo 1,4,9(1l) pregnatriene- 3,20-dione, 6e-methyl-l7a-hydroxy-21-fluoro 1,4,9( 11 pregnatriene-Zi,20dione.

EXAMPLE 42 6 a-meth yl-QaJ 1 p-dich lore-21 dado-1 7a-hydr0xy-I ,4- pregnadiene-3,20-di0ne 17-acetate A. 6e-methyl-17e-hydroxy-2l-iodo 1,4,9(11) pregnatriene-3,20-dione l7-acetate (the l-dehydro analog of the compound of Example 2 prepared according to the procedure of Example 41) is reacted with chlorine in carbon tetrachloride and the resultant product isolated and purified in the manner described in Example 3A to give 6a-methyl-9a,1lfl-dichloro-Zl-iodo-17a-hydroxy-L4- pregnadiene-3,20 -dione 17-acetate.

Alternatively, the compound of this example is prepared by the following procedure B.

B. 6u-methyl-9u,llfi-dichloro-21-iodo 17a hydroxyprogesterone l7-acetate (the compound of Example 3) is subjected to the action of a culture of the microorganism Corynebacterium simplex in the manner described in Example 41. The resultant product is isolated and purified in the described manner to give 6a-methyl-9u,ll 6-dichloro-2l-iodo 17a hydroxy-1,4-pregnadiene-3,20-dione 17-acetate.

Alternatively. the compound of this example is also prepared according to the following procedures C and D.

C Ga-METHYL-9a,1lB-DICHLORO-ZLIODO-l7a-HYDROXY- 1,4-PREGNADIENE3,20DIONE 6a-methyl-l7a-hydroxy 21 iodo 1,4,9(l1) pregnatriene-3 .20-dione (the compound of Example4l) is chlorinated by means of chlorine gas in carbon tetrachloride and the resultant product isolated and purified in the manner described in Example 3B to give 6a-methy1-9a,11fldichloro-Zl-iodo-l7u-hydroxy 1,4 pregnadiene 3,20- dione.

Alternatively, the compound of this example is prepared by subjecting 6a-methyl-9a,1lfl-dichloro-2l-iodo- 17a-hydroxyprogesterone (the compound of Example 33) to the action of a culture of Corynebacterium simplex as described in Example 41. The resultant product is isolated in the described manner and crystallized from acetone-hexane to give 6a-methyl-9a,llfl-dichloro-Zl-iodm l7a-hydroxy-1,4-pregnadiene-3 ,20-dione.

D. Ga-METHYL-QaJIfi'DICHLORO-21-IODO-1Ta-HYDROXY- 1,4-PREGNADIENE-3,20-DIONE 17-ACETATE The l7a-hydroxypregnadiene of Example 42C is esterified by means of acetic acid and trifiuoroacetic anhydride in the manner described in Example 2 to give oer-methyl- 9a.llfl-dichloro-Zl-iodo-Uni-hydroxy 1,4 pregnadiene- 3,20-dione l7-acetate.

Similarly, by substituting other lower alkanoic acids such as n-butyric and Valerie for acetic acid in the above procedure, the corresponding 17-esters are obtained, i.e. the l7-n-butyrate and 17-valerate of 6a-methyl-9u,1lpdichloro-Zl-iodo-lh-hydroxy 1,4 pregnadiene 3,20- dione.

EXAMPLE 43 6a-methyl-9a,11 8-dichIor0-2I-flu0r0-1 7a-hydroxy-1 ,4-

pregnadiene-SJO-dione 17-acetate A. 6a-methyl-17a-hydroxy 21 fiuoro-1,4,9(11)-preg natriene-3,20-dione l7-acetate (the l-dehydro analog of the compound of Example 4 prepared according to the procedure of Example 41) is chlorinated with N-chlorosuccinimide in the presence of hydrogen chloride. and lithium chloride in acetic acid in the manner described in Example 6A. The product is isolated in the described manner and crystallized from acetone-hexane to give 6:!- mCthyl-9oc,1 l fi-diChlOtO-Zl-flllOl'0-l7m-hYdIOXY-1,4 pregnadiene-3,20-dione 17-acetate.

Alternatively, the compound of this exampleis prepared according to the following procedure B.

B. 6a-methyl-9a,llfi-dichloroQI-fiuoro-lh hydroxyprogresterone 17-acetate (the compound of Example 6) is subjected to the action of a culture of Corynebacterium simplex in the manner described in Example 41 to give 6ct-mt3thyl-9a,llB-dlChlOlO-Zl-fiUOI'O 17c: hydroxy-1,4- pregnadiene-3,20-dione 17-acetate.

In similar manner, the compounds of Examples 7 through 11. 25, and 29 through 32 are subjected to the action of Corynebacterium simplex to give the corresponding A -dehydro analogs, i.e. 6a-methyl-9a-bromo l l fi-chloro-Zl-fluoro-l7m-hydroxy-l ,4-pregnadiene 3,20- dione l7-acetate, 6a-methyl-9iz-bromo 1118,21 difluorol7a-hydroxy-l,4-pregnadiene-3.20 dione l7 acetate, 61:- methyl-9a-iodo-l1 3-chloro-2l-fiuoro-17a hydroxy 1,4- pregnadiene-3,20-dione 17-acetate, 6a-methyl-9a,11fl-dichloro-2l-fluoro-l7a hydroxy 1,4 pregnadiene 3,20 dione l7-caproate, 6a-methyl-9a-bromo-l15,21 difluorol7a-hydroxy-1,4-pregnadiene-3,20-dione l7-caproate, 6a.-

fiuoro 9a,l lfi-dichloro-Zl-iodo-lhhydroxy 1,4 pregnadiene-3,20-dione 17-acetate, 6d,2l-dilluoro-9a,llfl-dichloro-l7a-hydroxy-1,4-pregnadiene 3,20 dione 17 acetate, 611,1lB,2l-trilluoro-9a-bromo 17a hydroxy 1,4- pregnadiene-3,20-dione 17'-acetate, 6:1,21 difiuoro 9aiodo-l 1,8-chloro-17u-hydroxy-1,4-pregnadiene-3,20 dione 17-acetate, and 6a,21-difiuoro-9a,1lfl-dichloro 17a hydroxyl ,4-pregnadiene-3,20-dione l7-caproate.

Another method for the preparation of the compound of this example, i.e. 6a-methyl-9a,llfl-dichloro-2l-fluoro- 17a-hydroxy-1,4-pregnadiene-3,20 dione 17-acetate, is described in following procedures C and D.

c. 6a-METHYL-9a,11BDICHLOR0-21-FLUORO'17e-HY- DROXY-Lt PREGNADIENE-3,20-DIONE 6a-methyl-2l-fluoro-l7a hydroxy 1,4,9(1l) pregnatriene-3,20-dione (the A -dehydro analog of the compound of Example 26 prepared according to the procedure of Example 41) is chlorinated with chlorine in carbon tetrachloride and the resultant product isolated and purified in the manner described in Example 3A to give 6oz-mBlhy1-9u,1lB-diChlOl'0-21-flUOI'0-17m hydroxy 1,4- pregnadiene-3,20-dione.

Alternatively, this compound is prepared by subjecting 6a-methyl-9a,llfl-dichloro-Zl-fiuoro 17a hydroxyprogresterone (the compound of Example 29B) to the action of a culture of Corynebacterium simplex in the manner described in Example 41.

In. like manner, the l7a-hydroxy halogenated proges terones of Examples 7B through 9B, 25B, and 295 through 313 are fermented with Corynebacterium sim' plex to yield respectively, 6a-methyl-9a-bromo-1l1S-chlo ro-21-fiuoro-17a-hydroxy-l ,4-pregnadiene-3,20-dione, 6a methyl-9a-bromo-l113,21-difluoro-l7a-hydroxy-1,4 preg nadiene-3,2O dione, 6m-methyl-9u-iodo-llfl chloro 21 fiuoro-l7a-hydroxy-l,4-pregnadiene-3,20 dione, 6a flu oro-2l-iodo-9a,1lfi-dichloro-lh hydroxy 1,4 pregna diene-3,20-dione, 6a,2l-difluoro-9u,1lfl-dichloro-l7a hy droxy-l ,4-pregnadiene-3,20-dione, 6a,1 15,2 l-trifluoro-9m bromo-l7a-hydroxy-l,4-pregnadiene-3,20 dione and 6a 2l-difluoro 9a-iodo-llfi-chloro-lh-hydroxy 1,4 preg nadiene-3,20-dione.

D. 6a-METHYL-9a.,1IB-DICHLORO-21-FLUORO17a-HY- DROXY-l,4-PREGNADIENE-3,20-DIONE 17-ACE'1ATE The 17u -hydroxy-1,4-pregnadiene of Example 43C i reacted with acetic acid and trifiuoroacetic anhydride ii the manner described in Example 2 to give 6a-methyl-9a 1lfi-dichloro-Zl-fluoro-Ua hydroxy 1,4 pregnadiene 3,20-dione 17-acetate.

Similarly, by substituting other lower alkanoic acid such as propionic and valeric for acetic acid in the abovl procedure, the corresponding 17-esters are obtained, is the 17-propionate and l7-valerate respectively of 6a methyl-901,1 l B-dichloroZl-fluoro-lh-hydroxy-IA preg nadiene-3,20-dione.

Also any of the l7a-hydroxy dihalogenated pregnadi enes obtained as described in above procedure 43C ar esterified with a lower alkanoic acid and trifiuoroaceti anhydride in the manner described above to give the cor responding 17-lower alkanoate esters.

EXAMPLE 44 6a,l 7 a-dimethyl-9a,1 I fl-dichloro-ZI -iod0-1 ,4-pregnadiene-3,20-di0ne 6d,l7a-dimethyl-2l-iodo-l,4,9(ll)-pregnadiene 3,2( dione (the A -dehydro analog of the compound of Ei ample 13 prepared as described in Example 41) is chlc rinated with chlorine gas in carbon tetrachloride in th presence of pyridine in the manner described in Exampl 3A to give 6a.l7a-dimethyl-9a,llfi-dichloro-Zl-iodo-L pregnadiene-3,20-dione.

Alternatively, the compound of this example is pn pared by subjecting 6a,l7a-dim6tl'1yl-9a,llfi-dichlOrO-ZI iodoprogesterone (the compound of Example 14) to th action of a culture of Corynebacterium simplex in th 23 nner described in Example 41 to give 6a,17u-dimethyll 1fl-dichloro-2l-iodo-1,4-pregnadiene-3 ,ZO-dione. in similar manner, by the action of a culture of the :roorganism Corynebacterium simplex, the compounds Examples 16 through 18, 34, 36 and 37 are converted their N-dehydro analogs, namely: l7a-dimethyl-9a, 1 1 }3-dichloro-2 1-fluoro-1,4-pregnaiiene-3,20-dione, l7a-dimethyl-9a-chloro1 1,6,2 l-difluoro-l ,4-pregnaiiene-3,20-dione, ,l7a-dimethyl-9a, 1 lB-dibromo-Zl-fluoro-1,4-pregnaiiene-3,20-dione, -fluoro-9a,1 1fl-dichloro-Zl-iodo-l7a-methyl-1,4- pregn-adiene-3,20-dione, ,2l-dlfiUO1O-9ml lp-dichloro-17a-methyl-1,4-pregna- :liene-3,20-dione, and ,21-difiu'oro-9 u-bromo-l 1flchloro-17a-methyl-1,4 pregnadiene-3,20-dione.

EXAMPLE 45 6a methyl 91,1118 dichloro 17a bromo 21- fluoro 1,4 pregnadiene 3,20 dione 6o: methyl 17a. bromo 21 fluoro 1,4,9(11)- :gnatriene-3,20-dione (prepared from the compound of .ampleZO by the procedure of Example 41) is chlori ted by means of N-chlorosuccinimide, hydrogen chlo- .e and lithium chloride in the manner described in ample 6A. The resultant product is isolated in the scribed manner and crystallized from acetone-hexane give 6a-methyl-9a,1 lfl-dichloro-17a-bromo-21-fluoro-l, aregnadiene-3,20-dione.

Alternatively, the compound of this example is prered by subjecting 6a-methyl-9a,11fl-dichloro17a-bro- )-21-fiuoroprogesterone (the compound of Example to the action of a culture of Corynebacterium simzx in the manner described in Example 41 to give 611- :thyl 9:1,115 dichloro 17o: bromo 21 fluorol-pregnadiene-3,20-dione.

In similar manner, the A -dehydro analogs of Examples 34 through 37 and 40 are prepared by the action of :ulture of Corynebacten'um simplex to give respectively, -methyl-9a,17a-dibromo1 lfl-chloro-Z 1 -fluoro- 1 ,4- pregnadiene-3,20-dione,

2,21-dlfll101'0-9a, 1 1 p-dichloro-lh-methyl-l ,4-pregnadiene-3,20-dione,

:,21-difluoro-9a,bromo-l 1fl-chloro-17a-methyl-L4- pregnadiene-3,20-dione, and

:,21-difluoro-9a, 1 1 fl-dichloro-lh-bromo- 1 ,4-pregnadiene-3,20-dione.

We claim:

1. A compound selected from the group consisting of pregnenes and the l-dehydro analogs thereof, said 4- 'egnenes having the formula:

herein X is a halogen having an atomic weight greater [an 19; Y is a halogen having an atomic weight less than 26 and being at least as electronegative as X; Z isa member of the group consisting of fluorine and iodine; and R is a member of the group consisting of methyl, bromine, hydroxy and acyloxy radicals of hydrocarbon carboxylic acids containing up to 12 carbon atoms.

2. 9a-X-l1,6-Y-17m-R-21-Z-6-fluoroprogesterone wherein X is a halogen having an atomic weight greater than 19; Y is a halogen having an atomieweight less than 126 and being at least as electronegative as X; Z is a member of the group consisting of fluorine and iodine; and R is an acyloxy radical of a hydrocarbon carboxylic acid containing up to 12 carbon atoms. a

3. 9oz-X-l1B-Y-l7a-R-2l-Z-6-flll0l'01 dehydroproges-' terone wherein X is a halogen having an atomic weight greater than 19; Y is a halogen having an atomic weight less than 126 and being at least as electronegative as X; Z is a member of the group consisting of fluorine and iodine; and R is an acyloxy radical of a hydrocarbon carboxylic acid containing up to 12 carbon atoms.

4. 6a-flll0l'0-9oz,lIfi-dlChlOl0-2l iodo 17a. hydroxy progesterone 17-acetate.

5. 6a-fluoro-9a,1lB-dichloro-2l-iodo-l7a hydroxy 1- dehydroprogesterone I'l -acetate.

6. 6a,21-difluoro-9a,1l,3 dichloro 17oz hydroxyprogesterone 17-acetate.

7. 60:,2l-difiUOIO-9a,llfl-dicl'llOl'O 17a hydroxyprogesterone l7-caproate.

8. 6a,l1,8,21-trifluoro-9a-bromo 17a hydroxyprogesterone l7-acetate.

9. A compound selected from the group consisting of 6a,21 -difiuoro-17a-bromo 9(11) dehydroprogesterone-'- and the l-dehydro analog thereof.

10. 9a-X-l1B-Y-2l-Z-6-fluoro 17a bromoprogesterone wherein X is a halogen having an atomic weight greater than 19; Y is a halogen having an atomic weight less than 126 and being at least as electronegative as X; and Z is halogen, of the group consisting of fluorine and iodine.

11. 9a-X-l1fi-Y-2l-Z-6-fiu0rO-l7a bromo-l-dehydroprogesterone wherein X is a halogen having an atomic weight greater than 19; Y is a halogen having an atomic weight less than 126 and being at least as electronegative as X; and Z is halogen, of the group consisting of fluorine and iodine.

12. 9a-X-11fl-Y-21-Z-6 fluoro 17oz hydroxyprogesterone wherein X is a halogen having an atomic weight greater than 19; Y is a halogen having an atomic weight less than 126 and being at least as electronegative as X; and Z is halogen, of the group consisting of fluorine and iodine.

13. 9a-X-1lfl-Y-Z1-Z-6-fluoro-l7u-hydroxy 1 dehydroprogesterone wherein X is a halogen having an atomic weight greater than 19; Y is a halogen having an atomic weight less than 126 and being at least as electronegative as X; and Z is halogen, of the group consisting of fluorine and iodine.

14. 6a-fiuoro-9a,llfl-dichloro-Zl-iodo 17a hydroxyprogesterone.

15. 6u-fluoro-9a,1lfl-dichloro-Zl-iodo-l7a-hydroxy 1- dehydroprogesterone.

16. 6a,21-difluoro-9a,1lfl-dichloro 17a hydroxyprogesterone.

17. 6a,21-difluoro-9a,1lp-dichloro 17a hydroxy 1- dehydroprogesterone.

18. 6a,115,21-trifluoro-9a-bromo-17a-hydroxy- 1 dehydroprogesterone.

19. 6u,21-difluoro9a,11B-dichloro-17a bromoprogesterone.

Magerlein et al June 10, 1958 Spero et al June 10, 1958 Lincoln et al Jan. 6, 1959 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 4-PREGNENES AND THE 1-DEHYDRO ANALOGS THEREOF, SAID 4PREGNENES HAVING THE FORMULA: 